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Transl. Med."],"published-print":{"date-parts":[[2026,8,26]]},"abstract":"<jats:p>\n                    Obesity imprints an epigenetic memory in adipose tissue macrophages (ATMs), allowing proinflammatory traits to persist after weight loss. However, mechanisms by which ATMs sustain efferocytosis and influence adipose tissue mass remain unclear. Here, we demonstrate that aberrant messenger RNA splicing, caused by dysfunction of the CWC22\/exon junction complex, limits efferocytosis in macrophages during postobesity weight loss. Multiomics and gene-targeting approaches revealed that 51.9% of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22.\n                    <jats:italic toggle=\"yes\">Scarb1<\/jats:italic>\n                    exon skipping increased scavenger receptor class B type II (SR-BII) expression, promoting the formation of SR-BI\/SR-BII heterodimers that were subsequently targeted for endoplasmic reticulum\u2013associated degradation. This reduced surface SR-BI in macrophages, suppressed efferocytosis and inosine release from dead cells, and impaired inosine-induced lipolysis in white adipose tissue. Restoring\n                    <jats:italic toggle=\"yes\">Scarb1<\/jats:italic>\n                    splicing with an antisense oligonucleotide rescued SR-BI expression, efferocytosis, inosine availability, and fat loss in\n                    <jats:italic toggle=\"yes\">Cwc22<\/jats:italic>\n                    -deficient mice. Immunohistochemical analysis of human adipose tissue specimens revealed predominant nuclear localization of CWC22 in ATMs from lean individuals, whereas this nuclear localization was markedly diminished in ATMs from obese individuals. These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adv0221","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:00:27Z","timestamp":1787767227000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Aberrant alternative splicing memorized in adipose tissue macrophages impedes efferocytosis during postobesity weight loss"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3354-0292","authenticated-orcid":true,"given":"Takuro","family":"Miyazaki","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Division of Biological Chemistry, SHOWA Medical University Graduate School of Pharmacy, Shinagawa-ku, Tokyo, 142-8555, Japan."},{"name":"Department of Biochemistry, SHOWA Medical University Graduate School of Medicine, Shinagawa-ku, Tokyo, 142-8555, Japan."},{"name":"Research Center for Biochemistry, SHOWA Medical University, Shinagawa-ku, Tokyo, 142-8555, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3456-3074","authenticated-orcid":true,"given":"Akira","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, 619-0284, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6983-8958","authenticated-orcid":true,"given":"Yuki","family":"Sugiura","sequence":"additional","affiliation":[{"name":"Multi-Omics Platform, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8315, Japan."},{"name":"Keio University Human Biology-Microbiome-Quantum Research 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